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Loss of Function of Ribonuclease T2, an Ancient and Phylogenetically Conserved Rnase, Plays a Crucial Role in Ovarian Tumorigenesis

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Loss of Function of Ribonuclease T2, an Ancient and Phylogenetically Conserved Rnase, Plays a Crucial Role in Ovarian Tumorigenesis Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis Francesco Acquatia, Marta Lualdia, Sabrina Bertilacciob, Laura Montia, Giovanna Turconia, Marco Fabbric, Annalisa Grimaldid, Achille Anselmoe, Antonio Inforzatoe, Angelo Collottac, Laura Cimettif, Cristina Rivaf, Laura Gribaldoc, Paolo Ghiab, and Roberto Taramellia,1 Departments of aTheoretical and Applied Sciences and dBiotechnology and Life Sciences, Università degli Studi dell’Insubria, 21100 Varese, Italy; bDepartment of Onco-Hematology, Clinical Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, 20132 Milan, Italy; cMolecular Biology and Genomics Unit, Institute for Health and Consumer Protection, Joint Research Centre, 21027 Ispra, Italy; eClinical and Research Institute Humanitas, 20089 Rozzano, Italy; and fDepartment of Pathology, Ospedale di Circolo, 21100, Varese, Italy Edited* by George Klein, Karolinska Institutet, Stockholm, Sweden, and approved April 3, 2013 (received for review December 18, 2012) In recent years, the role played by the stromal microenvironment The tumor microenvironment has recently become a crucial has been given growing attention in order to achieve a full under- player in the carcinogenetic processes (6–9). Indeed, stromal standing of cancer initiation and progression. Because cancer is a components such as fibroblasts, immune/vascular cells, and ECM tissue-based disease, the integrity of tissue architecture is a major are all known to be engaged in a complex and dynamic cross-talk constraint toward cancer growth. Indeed, a large contribution of the with the neighboring epithelium, which can crucially contribute natural resistance to cancer stems from stromal microenvironment to tumor suppression and resistance (6–9). Indeed, interaction of components, the dysregulation of which can facilitate cancer occur- parenchymal cells with stromal components is known to be es- rence. For instance, recent experimental evidence has highlighted sential for the maintenance of tissue architecture and function the involvement of stromal cells in ovarian carcinogenesis, as epit- (6–9), and several studies have documented the role played by omized by ovarian xenografts obtained by a double KO of the mu- the stroma as a key determinant of epithelial proliferation, cell GENETICS Dicer Pten rine and genes. Likewise, we reported the role of an death, motility, polarity, and differentiation (6, 9). Moreover, ancient extracellular RNase, called Ribonuclease T2 (RNASET2), stromal abnormalities have long been known to exert profound within the ovarian stromal microenvironment. Indeed, hyperexpres- influences on tumor induction and progression (6–9). However, RNASET2 sion of is able to control tumorigenesis by recruiting mac- although the notion of a dominant role of the microenvironment rophages (mostly of the anticancer M1 subtype) at the tumor sites. in providing signaling cues to suppress or revert a malignant We present biological data obtained by RNASET2 silencing in the – RNASET2 phenotype is consolidated (6 9), a detailed understanding of the poorly tumorigenetic and highly -expressing human types and specific roles of stromal and immune cells and of the OVCAR3 cell line. RNASET2 knockdown was shown to stimulate in ECM dynamics within it is still lacking. vivo tumor growth early after microinjection of OVCAR3 cells in Our research group has recently contributed to this issue by in- nude mice. Moreover, we have investigated by molecular profiling vestigating the role of the human RNASET2 gene (10–15). The the in vivo expression signature of human and mouse cell xeno- latter codes for an extracellular RNase expressed in several tissues, grafts and disclosed the activation of pathways related to activation of the innate immune response and modulation of ECM compo- including the ovary and tubal structures, and is highly conserved nents. Finally, we provide evidence for a role of RNASET2 in trigger- among phyla from viruses to humans, implying a crucial, evolu- ing an in vitro chemotactic response in macrophages. These results tionary conserved function (16). In an ovarian cancer xenograft further highlight the critical role played by the microenvironment in model, we previously found RNASET2 to carry out a strong onco- RNASET2-mediated ovarian tumor suppression, which could even- suppressive activity associated with an in vivo recruitment of mac- tually contribute to better clarify the pathogenesis of this disease. rophages into the tumor mass (15). Here, we report RNASET2 gene silencing in an independent ovarian cancer cell model to provide further evidence for its role in microenvironmental-mediated tumor espite its relatively low incidence rate, ovarian cancer is an suppression in vivo. Dextremely lethal disease, which globally claims 125,000 lives per year, making it the seventh leading cause of cancer-related Results deaths among women (1). Although the 5-y survival rate for stage I RNASET2 Silencing in OVCAR3 Ovarian Cancer Cells Is Associated with ovarian cancer is >90%, stage I diagnoses are more often the Increased in Vivo Tumorigenesis. Ovarian cancer-derived OVCAR3 exception than the rule. Indeed, most patients present with cells were used to investigate the effects of RNASET2 knock- advanced-stage tumors, for which the 5-y survival rate is a dismal down. This cell line was chosen on two main basic premises. 30% (1). Contributing to such a dramatic outlook is the rather poor First, RNASET2 transcript and protein levels are significantly understanding of the biological basis of the disease, which appears higher compared with other ovarian cancer cell lines (10). as a highly heterogeneous group of pathological entities (2, 3). Traditionally, the anatomical site from which most cases of ovarian cancer were thought to arise has been the ovarian surface epithe- Author contributions: F.A. and R.T. designed research; M.L., S.B., L.M., G.T., M.F., A.G., A.A., lium (2, 3). This long-held belief has recently been challenged by A.I., A.C., L.C., C.R., and L.G. performed research; F.A., C.R., L.G., P.G., and R.T. analyzed several observations pointing to fallopian tube structures as the data; and F.A. and R.T. wrote the paper. prevailing sites where insurgence of ovarian neoplasias occurs (4). The authors declare no conflict of interest. According to this new paradigm, the ovary would rather represent *This Direct Submission article had a prearranged editor. “ ” a sort of metastatic secondary site, the primary site being local- Data deposition: The data reported in this paper have been deposited in the Gene Ex- ized in the fallopian tube parenchyma (4). Supporting this para- pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE43029). digm is a recent finding from Dicer/Pten double KO mice, in which 1To whom correspondence should be addressed. E-mail: [email protected]. ovarian carcinogenesis is initiated from abnormal proliferation This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. within the stromal compartment of the fallopian tube (5). 1073/pnas.1222079110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1222079110 PNAS Early Edition | 1of6 Downloaded by guest on September 24, 2021 Second, OVCAR3 cells are reported to be poorly tumorigenic in in control tumors, that was already observed in histological sec- vivo (17). RNASET2 silencing was carried out in OVCAR3 cells tions, was also confirmed by IHC analysis (Fig. S1). by stably expressing an siRNA targeting the RNASET2 mRNA, A relevant histological finding concerned the presence of in- resulting in complete abrogation of its expression (Fig. 1A). flammatory infiltrates in xenografts from control OVCAR3 cells. Three independent RNASET2 knockdown clones and three To characterize the nature of such infiltrating cells, we carried out control clones (expressing a scrambled shRNA) were then cho- IHC assays for several inflammatory markers (data not shown). sen for further analyses. The clones were injected s.c. into nude Among the chosen markers the most significant was CD68, whose mice, and tumor growth was followed for approximately 40 d. As pattern pointed to the presence of murine macrophages as the most depicted in Fig. 1B, after a few days of in vivo growth, the three representative cell population of the infiltrate, as shown in Fig. 2 G RNASET2-silenced clones showed an increased growth kinetics and H. To discriminate between macrophage subpopulations, we compared with control clones. By the end of the in vivo assay, the carried out an IHC assay for markers able to differentiate the M1 average tumor weight from RNASET2-silenced xenografts was and M2 macrophage cell subpopulations. As shown in Fig. 2 I and also significantly increased compared with control xenografts J, a consistent depletion of inducible nitric oxide synthase-positive (Fig. 1C). We thus concluded that RNASET2 silencing conferred M1 macrophages was observed in RNASET2-silenced tumors com- to the poorly tumorigenic OVCAR3 cell line an increased in vivo pared with control xenografts. By contrast, infiltration by dectin-1– growth rate. Such behavior is substantially congruent with what positive M2 macrophages, which was less pronounced in control we have previously reported following overexpression of RNASET2 xenografts compared with M1 macrophages, was only slightly de- into the highly tumorigenic, low RNASET2-expressing Hey3Met2 creased in RNASET2-silenced tumors (Fig. 2 K and L). In
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